Barrier layer

ABSTRACT

A barrier layer and corresponding method of making provide anti-inflammatory, non-inflammatory, and anti-adhesion functionality for a medical device implantable in a patient. The barrier layer can be combined with a medical device structure to provide anti-adhesion characteristics, in addition to improved healing, non-inflammatory, and anti-inflammatory response. The barrier layer is generally formed of a naturally occurring oil, or an oil composition formed in part of a naturally occurring oil, that is at least partially cured forming a cross-linked gel. In addition, the oil composition can include a therapeutic agent component, such as a drug or other bioactive agent.

RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 11/237,420 (now U.S. Pat. No. 9,801,913 B2), which was filed onSep. 28, 2005, and which claims priority to, and the benefit of, U.S.Provisional Application No. 60/613,808, filed Sep. 28, 2004. Thedisclosures of the above mentioned applications and patent are herebyincorporated by reference in their entirety for all they disclose.

FIELD OF THE INVENTION

The present invention relates to barrier layers, and more particularlyto a barrier layer that is able to deliver therapeutic agents to atargeted location and also to adhere to a medical device.

BACKGROUND OF THE INVENTION

Biocompatible medical film is often used in surgical settings. Forexample, Seprafilm®, a product of Genzyme Corporation of Cambridge,Mass., is used in patients undergoing abdominal or pelvic laparotomy asan adjunct intended to reduce the incidence, extent, and severity ofpostoperative adhesions between different tissues and organs andimplantable medical devices such as soft tissue support membranes andmesh.

U.S. Pat. No. 5,017,229 is directed to a water insoluble, biocompatiblegel that includes the reaction product of hyaluronic acid, a polyanionicpolysaccharide, and an activating agent. The gel described in the '229patent can be provided in the form of an adhesion preventioncomposition, such as a membrane or composition suitable forincorporation into a syringe. The gel is described as being able to forma film by being compressed or allowed to dehydrate. When modified withpolysaccharide, the film forms the above-described Seprafilm®anti-adhesion or adhesion barrier product.

However, such commercially available adhesion prevention and adhesionbarrier products often are difficult to handle and apply to the targetedlocation due to their chemical make up and bio-dissolvable properties.The composition and structural properties of these bio-dissolvableproducts require that they be handled with dry hands or instruments,which can be difficult during most surgical intervention operations.Furthermore, many of these bio-dissolvable films are made intentionallyto be thin to minimize tissue disruption and consequently end up beingstructurally weak (i.e., easily torn or folded during handling).

Surgical meshes also can have anti-adhesion properties. PCT ApplicationPublication No. WO 2004/028583 is directed to compositions, devices, andmethods for maintaining or improving the integrity of body passagewaysfollowing surgery or injury. The delivery devices can include one ormore therapeutic agents provided with a mesh wrap. The mesh is mostoften constructed of a synthetic polymer material, such as polyethylene,polytetrafluoroethylene, and polypropylene, and can include a carrierhaving a therapeutic agent attached thereto or coated thereon. The meshstructure makes it easier to handle the device without the drawbacks offilm, namely tearing and folding.

Some of these film and mesh devices also include therapeutic agents incombination with the anti-adhesion properties. PCT ApplicationPublication No. WO 03/028622 is directed to a method of delivering drugsto a tissue using drug coated medical devices. The drug coated medicaldevice is brought into contact with the target tissue or circulation andthe drugs are quickly released onto the area surrounding the device in ashort period of time after contact is made. The release of the drug mayoccur over a period of 30 seconds, 1 minute or 3 minutes. In oneembodiment described in the publication, the carrier of the drug is aliposome. Other particles described as potential drug carriers includelipids, sugars, carbohydrates, proteins, and the like. The publicationdescribes these carriers as having properties appropriate for a quickshort term release of a drug combined with the carriers.

SUMMARY OF THE INVENTION

What is desired is a non-polymeric biological oil based barrier layerwhich exhibits anti-adhesion properties without chronic inflammation tothe local tissue that can also be further enhanced with the applicationof one or more therapeutic agents or medications for absorption into thetissue that is in contact with the biological oil layer or coating. Thebarrier layer can also be coated, mounted or adhered to a medicaldevice. The present invention is directed toward further solutions toaddress this need.

In accordance with one embodiment of the present invention, a barrierlayer device includes a medical device structure and a barrier layerformed on at least a portion of the medical device structure. Thebarrier layer is formed of a non-polymeric cross-linked gel.

It should be noted that the term cross-linked gel, as utilized hereinwith reference to the present invention, refers to a gel that isnon-polymeric and is derived from an oil composition comprisingmolecules covalently cross-linked into a three-dimensional network byone or more of ester, ether, peroxide, and carbon-carbon bonds in asubstantially random configuration. In various preferred embodiments,the oil composition comprises a fatty acid molecule, a glyceride, andcombinations thereof.

In accordance with aspects of the present invention, the medical deviceis in the form of a biocompatible mesh. The cross-linked gel is derivedfrom at least one fatty acid compound. The barrier layer can be abiological oil barrier, a physical anti-adhesion barrier, or acombination thereof.

In accordance with further aspects of the present invention, thecross-linked gel is formed of an oil or oil composition that is at leastpartially cured. The cross-linked gel can be a biological oil that is atleast partially cured, including fish oil or other oils, including thoseoils containing lipids and/or omega-3 fatty acids.

Curing with respect to the present invention generally refers tothickening, hardening, or drying of a material brought about by heat, UVlight, chemical means, and/or reactive gasses.

In accordance with further aspects of the present invention, the barrierlayer includes at least one therapeutic agent component. The therapeuticagent component can include an agent selected from the group consistingof antioxidants, anti-inflammatory agents, anti-coagulant agents, drugsto alter lipid metabolism, anti-proliferatives, anti-neoplastics, tissuegrowth stimulants, functional protein/factor delivery agents,anti-infective agents, imaging agents, anesthetic agents,chemotherapeutic agents, tissue absorption enhancers, anti-adhesionagents, germicides, analgesics, prodrugs, and antiseptics.

In accordance with further aspects of the present invention, the barrierlayer includes a plurality of tiers. A first tier can be configured onthe medical device structure and a second tier configured on the firsttier, wherein the first tier is cured to a greater extent than thesecond tier. Alternatively, a first tier can be configured on themedical device structure and a second tier configured on the first tier,wherein the second tier is cured to a greater extent than the firsttier.

In accordance with further aspects of the present invention, the barrierlayer is configured to provide controlled release of a therapeutic agentcomponent.

In accordance with further aspects of the present invention, the barrierlayer includes an oil composition that includes an oil component incombination with at least one of an additional oil component, atherapeutic agent component, a solvent, and a preservative. The barrierlayer is bio-absorbable. The biological oil barrier layer maintainsanti-inflammatory and/or non-inflammatory properties.

In accordance with aspects of the present invention, the barrier layeris formed of a cured cross-linked gel derived from at least one fattyacid compound and containing an interdispersed biological oil, such thatthe cured cross-linked gel and the biological oil create a biologicaloil barrier and a physical anti-adhesion barrier on the medical device.

The barrier layer can be configured on one side of the medical devicestructure, on a portion of one side of the medical device structure,and/or on two sides of the medical device structure.

The barrier layer can further include alpha tocopherol or a derivativeor analog thereof to at least partially form the barrier layer.

In accordance with one embodiment of the present invention, a barrierlayer device includes a biocompatible mesh structure, and a barrierlayer formed on at least a portion of the mesh structure. The barrierlayer is formed of a non-polymeric cross-linked gel providing abiological oil barrier and a physical anti-adhesion barrier.

In accordance with one embodiment of the present invention, a method ofmaking a barrier layer device includes providing a medical devicestructure, and creating a barrier layer formed on at least a portion ofthe medical device structure. The barrier layer is formed of anon-polymeric cross-linked gel.

In accordance with aspects of the present invention, creating thebarrier layer includes providing a biological oil or oil composition,applying the oil or oil composition to the medical device structure, andcuring the oil or oil composition on the medical device structure toform the barrier layer. In accordance with further aspects of thepresent invention, the method further includes partially curing thebiological oil or oil composition prior to applying the oil or oilcomposition to the medical device structure to thicken the oil or oilcomposition.

In accordance with further aspects of the present invention, the methodfurther includes applying the oil or oil composition using multipletiers. An additional tier of oil or oil composition can likewise beapplied after curing the oil or oil composition on the medical device.

In accordance with further aspects of the present invention, the step ofcuring includes applying a curing mechanism, such as heat, UV light,chemical means, or reactive gases.

BRIEF DESCRIPTION OF THE DRAWINGS

The aforementioned features and advantages, and other features andaspects of the present invention, will become better understood withregard to the following description and accompanying drawings, wherein:

FIG. 1 is a diagrammatic illustration of a barrier layer realized as astand alone film, according to one embodiment of the present invention;

FIGS. 2A, 2B, and 2C are cross-sectional views of the barrier layer inaccordance with one aspect of the present invention;

FIGS. 3A, 3B, 3C, 3D, 3E, and 3F are diagrammatic views of the barrierlayer in accordance with another aspect of the present invention;

FIG. 4 is a flow chart illustrating a method of making the barrier layerof the present invention, in accordance with one embodiment of thepresent invention;

FIGS. 5A and 5B are perspective and cross-sectional views of the barrierlayer in combination with a medical device, in accordance with oneembodiment of the present invention;

FIG. 6 is a flow chart illustrating a method of combining the barrierlayer with a medical device, in accordance with one embodiment of thepresent invention;

FIG. 7 is a flow chart illustrating another variation of the method ofFIG. 6, in accordance with one embodiment of the present invention; and

FIGS. 8A, 8B, and 8C are diagrammatic illustrations of the barriercoupled with various medical devices.

DETAILED DESCRIPTION

An illustrative embodiment of the present invention relates to theprovision of a barrier layer that can exhibit anti-inflammatoryproperties, non-inflammatory properties, and anti-adhesion properties,and corresponding method of making. The barrier layer can be its ownmedical device (i.e., a stand alone film), or the barrier layer can becombined with another medical device to provide anti-adhesioncharacteristics, in addition to improved healing and delivery oftherapeutic agents. The barrier layer is generally formed of a naturallyoccurring oil, or an oil composition formed in part of a naturallyoccurring oil. In addition, the oil composition can include atherapeutic agent component, such as a drug or other bioactive agent.The barrier layer is implantable in a patient for short term or longterm applications, and can include controlled release of the therapeuticagent. As implemented herein, the barrier layer is a non-polymericcross-linked gel derived at least in part from a fatty acid compound.

As utilized herein, the term “bio-absorbable” generally refers to havingthe property or characteristic of being able to penetrate the tissue ofa patient's body. In certain embodiments of the present inventionbio-absorption occurs through a lipophilic mechanism. The bio-absorbablesubstance is soluble in the phospholipid bi-layer of cells of bodytissue, and therefore impacts how the bio-absorbable substancepenetrates into the cells.

It should be noted that a bio-absorbable substance is different from abiodegradable substance. Biodegradable is generally defined as capableof being decomposed by biological agents, or capable of being brokendown by microorganisms or biological processes, in a manner that doesnot result in cellular uptake of the biodegradable substance.Biodegradation thus relates to the breaking down and distributing of asubstance through the patient's body, verses the penetration of thecells of the patient's body tissue. Biodegradable substances, such aspolymers, can cause inflammatory response due to either the parentsubstance or those substances formed during breakdown, and they may ormay not be absorbed by tissues. Bio-absorbable substances break downinto substances or components that do not cause an inflammatory responseand can be consumed by the cells forming the body tissues.

The phrase “controlled release” generally refers to the release of abiologically active agent in a predictable manner over the time periodof weeks or months, as desired and predetermined upon formation of thebiologically active agent on the medical device from which it is beingreleased. Controlled release includes the provision of an initial burstof release upon implantation, followed by the predictable release overthe aforementioned time period.

With regard to the aforementioned oils, it is generally known that thegreater the degree of unsaturation in the fatty acids the lower themelting point of a fat, and the longer the hydrocarbon chain the higherthe melting point of the fat. A polyunsaturated fat, thus, has a lowermelting point, and a saturated fat has a higher melting point. Thosefats having a lower melting point are more often oils at roomtemperature. Those fats having a higher melting point are more oftenwaxes or solids at room temperature. Therefore, a fat having thephysical state of a liquid at room temperature is an oil. In general,polyunsaturated fats are liquid oils at room temperature, and saturatedfats are waxes or solids at room temperature.

Polyunsaturated fats are one of four basic types of fat derived by thebody from food. The other fats include saturated fat, as well asmonounsaturated fat and cholesterol. Polyunsaturated fats can be furthercomposed of omega-3 fatty acids and omega-6 fatty acids. Under theconvention of naming the unsaturated fatty acid according to theposition of its first double bond of carbons, those fatty acids havingtheir first double bond at the third carbon atom from the methyl end ofthe molecule are referred to as omega-3 fatty acids. Likewise, a firstdouble bond at the sixth carbon atom is called an omega-6 fatty acid.There can be both monounsaturated and polyunsaturated omega fatty acids.

Omega-3 and omega-6 fatty acids are also known as essential fatty acidsbecause they are important for maintaining good health, despite the factthat the human body cannot make them on its own. As such, omega-3 andomega-6 fatty acids must be obtained from external sources, such asfood. Omega-3 fatty acids can be further characterized as containingeicosapentaenoic acid (EPA), docosahexanoic acid (DHA), andalpha-linolenic acid (ALA). Both EPA and DHA are known to haveanti-inflammatory effects and wound healing effects within the humanbody.

Oil that is hydrogenated becomes a waxy solid. Attempts have been madeto convert the polyunsaturated oils into a wax or solid to allow the oilto adhere to a device for a longer period of time. One such approach isknown as hydrogenation, which is a chemical reaction that adds hydrogenatoms to an unsaturated fat (oil) thus saturating it and making it solidat room temperature. This reaction requires a catalyst, such as a heavymetal, and high pressure. The resultant material forms a non-crosslinkedsemi-solid. Hydrogenation can reduce or eliminate omega-3 fatty acids,and any therapeutic effects (both anti-inflammatory and wound healing)they offer.

For long term controlled release applications, polymers, as previouslymentioned, have been utilized in combination with a therapeutic agent.Such a combination provides a platform for the controlled long termrelease of the therapeutic agent from a medical device. However,polymers have been determined to themselves cause inflammation in bodytissue. Therefore, the polymers often must include at least onetherapeutic agent that has an anti-inflammatory effect to counter theinflammation caused by the polymer delivery agent. In addition, patientsthat receive a polymer-based implant must also follow a course ofsystemic anti-inflammatory therapy, to offset the inflammatoryproperties of the non-absorbable polymer. Typical anti-inflammatoryagents are immunosupressants and systemic delivery of anti-inflammatoryagents can sometimes lead to additional medical complications, such asinfection or sepsis, which can lead to long term hospitalization ordeath. Use of the non-polymeric cross-linked gel of the inventivecoating described herein can negate the necessity of anti-inflammatorytherapy, and the corresponding related risks described, because there isno inflammatory reaction to the oil barrier.

In addition, some curing methods have been indicated to have detrimentaleffects on the therapeutic agent combined with the omega-3 fatty acid,making them partially or completely ineffective. As such, oils, and morespecifically oils containing omega-3 fatty acids, have been utilized asa delivery agent for the short term uncontrolled release of atherapeutic agent, so that minimal or no curing is required. However,there are no known uses of oils containing omega-3 fatty acids forcombination with a therapeutic agent in a controlled release applicationthat makes use of the therapeutic benefits of the omega-3 fatty acids.Further, some heating of the omega-3 fatty acids to cure the oil canlessen the total therapeutic effectiveness of the omega-3 fatty acids,but not eliminate the therapeutic effectiveness. One characteristic thatcan remain after certain curing by heating methods is thenon-inflammatory response of the tissue when exposed to the curedomega-3 fatty acid material. As such, an oil containing omega-3 fattyacids can be heated for curing purposes, and still maintain some or evena majority of the therapeutic effectiveness of the omega-3 fatty acids.In addition, although the therapeutic agent combined with the omega-3fatty acid and cured with the omega-3 fatty acid can be renderedpartially ineffective, the portion remaining of the therapeutic agentcan, in accordance with the present invention, maintain pharmacologicalactivity and in some cases be more effective than an equivalent quantityof agent delivered with other barrier or coating materials.

It should be noted that as utilized herein to describe the presentinvention, the term vitamin E and the term alpha-tocopherol, areintended to refer to the same or substantially similar substance, suchthat they are interchangeable and the use of one includes an implicitreference to both. Further included in association with the term vitaminE are such variations including but not limited to one or more ofalpha-tocopherol, beta-tocopherol, delta-tocopherol, gamma-tocopherol,alpha-tocotrienol, beta-tocotrienol, delta-tocotrienol,gamma-tocotrienol, alpha-tocopherol acetate, beta-tocopherol acetate,gamma-tocopherol acetate, delta-tocopherol acetate, alpha-tocotrienolacetate, beta-tocotrienol acetate, delta-tocotrienol acetate,gamma-tocotrienol acetate, alpha-tocopherol succinate, beta-tocopherolsuccinate, gamma-tocopherol succinate, delta-tocopherol succinate,alpha-tocotrienol succinate, beta-tocotrienol succinate,delta-tocotrienol succinate, gamma-tocotrienol succinate, mixedtocopherols, vitamin E TPGS, derivatives, analogs and pharmaceuticallyacceptable salts thereof.

FIGS. 1 through 8C, wherein like parts are designated by like referencenumerals throughout, illustrate an example embodiment of a non-polymericbiological and physical oil barrier layer according to the presentinvention. Although the present invention will be described withreference to the example embodiments illustrated in the figures, itshould be understood that many alternative forms can embody the presentinvention. One of ordinary skill in the art will additionally appreciatedifferent ways to alter the parameters of the embodiments disclosed,such as the size, shape, or type of elements or materials, in a mannerstill in keeping with the spirit and scope of the present invention.

FIG. 1 illustrates a non-polymeric biological oil barrier layer 10 inaccordance with one embodiment of the present invention. The barrierlayer 10 is flexible, to the extent that it can be placed in a flat,curved, or rolled, configuration within a patient. The barrier layer 10is implantable, for both short term and long term applications.Depending on the particular formulation of the barrier layer 10, thebarrier layer 10 will be present after implantation for a period ofhours to days, or possibly months.

The barrier layer 10 is formed of an oil component. The oil componentcan be either an oil, or an oil composition. The oil component can be anaturally occurring oil, such as fish oil, cod liver oil, cranberry oil,or other oils having desired characteristics. One example embodiment ofthe present invention makes use of a fish oil in part because of thehigh content of omega-3 fatty acids, which provide healing support fordamaged tissue, as discussed below. The fish oil also serves as ananti-adhesion agent. In addition, the fish oil maintainsanti-inflammatory or non-inflammatory properties as well. The presentinvention is not limited to formation of the film with fish oil as thenaturally occurring oil. However, the following description makesreference to the use of fish oil as one example embodiment. Othernaturally occurring oils can be utilized in accordance with the presentinvention as described herein.

It should be noted that as utilized herein, the term fish oil fatty acidincludes but is not limited to omega-3 fatty acid, fish oil fatty acid,free fatty acid, monoglycerides, di-glycerides, or triglycerides, estersof fatty acids, or a combination thereof. The fish oil fatty acidincludes one or more of arachidic acid, gadoleic acid, arachidonic acid,eicosapentaenoic acid, docosahexaenoic acid or derivatives, analogs andpharmaceutically acceptable salts thereof. Furthermore, as utilizedherein, the term free fatty acid includes but is not limited to one ormore of butyric acid, caproic acid, caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid,gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,analogs and pharmaceutically acceptable salts thereof. The naturallyoccurring oils, including fish oil, are cured as described herein toform a hydrophobic cross-linked gel, creating the barrier layer 10.

It should further be noted that FIG. 1 represents merely one embodimentof the barrier layer 10. The barrier layer 10 serves as a biological oilbarrier and, depending on degree of cure, can also serve as a physicalbarrier, as depicted. The biological oil barrier is represented by theapplication of the fatty acid based oil, such as fish oil, onto amedical device. Such a configuration provides a biological oil barrierlayer that provides a non-inflammatory or anti-inflammatory barriercoating. Using a number of different methods as described below, thebiological oil can be cured to create a non-polymeric cross-linked gel.In the instance of the medical device taking the form of a surgicalmesh, the biological oil can be cured to the extent that the cells orpores of the mesh are substantially or completely bridged by the curedbiological oil creating a physical barrier. With such a configurationthere remains some biological oil that is not cured but isinterdispersed within the cured oil and maintains the biological oilbarrier layer as well. Thus, substantial curing creates both abiological oil barrier layer and a physical barrier. The physicalbarrier provides anti-adhesive properties of the barrier as discussedherein. Additional embodiments can include the provision of thesubstantially cured oil forming the biological oil barrier layer withphysical layer, and then a subsequent application of the biological oilas a top coat. This creates a more substantial biological oil barrierlayer supported by the combination biological oil barrier layer andphysical barrier layer.

One aspect of the barrier layer 10 mentioned above is that it hasanti-adhesion characteristics or properties. By anti-adhesion, what ismeant is a characteristic whereby the incidence, extent, and severity ofpostoperative adhesions, or other lacerations or tissue injuries,between different tissues and organs is reduced. The anti-adhesioncharacteristic results from the materials used to form the barrier layer10.

More specifically, the barrier layer 10 provides a lubricious and/oranti-adhesive surface against tissue. The barrier layer 10 itself, inits substantially cured configuration, can provide a physicalanti-adhesion barrier between two sections of tissue, or the barrierlayer 10 can form an anti-adhesion surface on a medical device, such asthe mesh 40. The use of the naturally occurring oil, such as fish oil,provides extra lubrication to the surface of the medical device, whichhelps to reduce injury. With less injury, there is less of aninflammatory response, and less healing required. The biological oilbarrier created by the fatty acid oil derived barrier layer likewiseprovides anti-inflammatory properties, thus reducing the occurrence ofinflammatory response and also adhesions due to inflammation. The oilysurface of the barrier layer 10 provides the anti-adhesioncharacteristics. One of ordinary skill in the art will appreciate thatdifferent oils will have different anti-adhesive properties, and theoils can be modified to be more liquefied or more solid or waxy, asdesired. Accordingly, the degree of anti-adhesive properties offered bythe barrier layer 10 can vary. The modification of the oils from a moreliquid physical state to a more solid, but still flexible, physicalstate is implemented through the curing process. As the oils are cured,especially in the case of fatty acid-based oils such as fish oil,cross-links form creating a gel. As the curing process is performed overincreasing time durations and/or increasing temperature or intensityconditions, more cross-links form transitioning the gel from arelatively liquid gel to a relatively solid-like, but still flexible,gel structure.

Another aspect of the present invention is that the barrier layer 10 isformed of the bio-absorbable material, such as naturally occurring fishoil, in accordance with the example embodiment described herein. Thebio-absorbable properties of the naturally occurring oil enable thebarrier layer 10 to be absorbed by the cells of the body tissue (i.e.,bio-absorbable). In example embodiments of the present invention, thebio-absorbable barrier layer contains lipids, many of which originate astriglycerides. It has previously been demonstrated that triglyceridebyproducts, such as partially hydrolyzed triglycerides and fatty acidmolecules can integrate into cellular membranes and enhance thesolubility of drugs into the cell. Whole triglycerides are known not toenhance cellular uptake as well as partially hydrolyzed triglyceride,because it is difficult for whole triglycerides to cross cell membranesdue to their relatively larger molecular size. Vitamin E compounds canalso integrate into cellular membranes resulting in decreased membranefluidity and cellular uptake.

Compounds that move too rapidly through a tissue may not be effective inproviding a sufficiently concentrated dose in a region of interest.Conversely, compounds that do not migrate in a tissue may never reachthe region of interest. Cellular uptake enhancers such as fatty acidsand cellular uptake inhibitors such as alpha-tocopherol can be usedalone or in combination to provide an effective transport of a givencompound to a given region or location. Both fatty acids andalpha-tocopherol are accommodated by the barrier layer of the presentinvention described herein. Accordingly, fatty acids andalpha-tocopherol can be combined in differing amounts and ratios tocontribute to a barrier layer in a manner that provides control over thecellular uptake characteristics of the barrier layer and any therapeuticagents mixed therein.

For example, the amount of alpha-tocopherol can be varied in the barrierlayer. Alpha-tocopherol is known to slow autoxidation in fish oil byreducing hydroperoxide formation, which results in a decrease in theamount of cross-linking in cured fish oil. In addition alpha-tocopherolcan be used to increase solubility of drugs in the fish oil forming thebarrier layer. Thus, varying the amount of alpha-tocopherol present inthe barrier layer can impact the resulting formation. Alpha-tocopherolcan actually protect the therapeutic drug during curing, which increasesthe resulting drug load in the barrier layer after curing. Furthermore,with certain therapeutic drugs, the increase of alpha-tocopherol in thebarrier layer serves to slow and extend drug release due to theincreased solubility of the drug in the alpha-tocopherol component ofthe barrier layer. This reflects the cellular uptake inhibitorfunctionality of alpha-tocopherol, in that the uptake of the drug isslowed and extended over time.

It should further be emphasized that the bio-absorbable nature of thebarrier layer results in the barrier layer 10 being completely absorbedover time by the cells of the body tissue. There are no substances inthe barrier layer, or break down products of the barrier layer, thatinduce an inflammatory response. The barrier layer 10 is generallycomposed of, or derived from, omega-3 fatty acids bound totriglycerides, potentially also including a mixture of free fatty acidsand vitamin E (alpha-tocopherol). The triglycerides are broken down bylipases (enzymes) which result in free fatty acids that can than betransported across cell membranes. Subsequently, fatty acid metabolismby the cell occurs to metabolize any substances originating with thebarrier layer. The bio-absorbable nature of the barrier layer of thepresent invention results in the barrier layer being absorbed over time,leaving only an underlying delivery or other medical device structurethat is biocompatible. There is no foreign body inflammatory response tothe bio-absorbable barrier layer.

Although the present invention is bio-absorbable to the extent that thebarrier layer 10 experiences the uptake into or through body tissues, inthe specific embodiment described herein formed using naturallyoccurring oils, the exemplar oils are also lipid based oils. The lipidcontent of the oils provides a highly bio-absorbable barrier layer 10.More specifically, there is a phospholipids layer in each cell of thebody tissue. The fish oil, and equivalent oils, contain lipids as well.There is a lipophilic action that results where the lipids are attractedby each other in an effort to escape the aqueous environment surroundingthe lipids.

A further aspect of the barrier layer 10 is that the specific type ofoil can be varied, and can contain elements beneficial to healing. Thebarrier layer also provides a natural scaffold for cellular growth andremodeling with clinical applications in general surgery, spinal repair,orthopedic surgeries, tendon and ligament repairs, gynecological andpelvic surgeries, and nerve repair applications. The addition oftherapeutic agents to the films used in these applications can beutilized for additional beneficial effects, such as pain relief orinfection minimization. In addition, non-surgical applications includeexternal wound care, such as a treatment for burns or skin ulcers,without therapeutics as a clean, non-permeable, non-adhesive,anti-inflammatory, non-inflammatory dressing, or with added therapeuticsfor additional beneficial effects. The film may also be used as atransdermal drug delivery patch.

The process of wound healing involves tissue repair in response toinjury and it encompasses many different biologic processes, includingepithelial growth and differentiation, fibrous tissue production andfunction, angiogenesis, and inflammation. The inventive cross-linked gelhas been shown in an animal model not to produce an inflammatoryresponse, but still provide excellent cellular overgrowth with little tono fibrous capsule formation. Accordingly, the cross-linked gel providesan excellent material suitable for wound healing applications.

Another aspect of the barrier layer 10 mentioned above is that thebarrier layer 10 can contain therapeutic agents for delivery to the bodytissue. Therapeutic agents have been delivered to a targeted location ina human utilizing a number of different methods in the past. Forexample, agents may be delivered nasally, transdermally, intravenously,orally, or via other conventional methods. Delivery may vary by releaserate (i.e., quick release or slow release). Delivery may also vary as tohow the drug is administered. Specifically, a drug may be administeredlocally to a targeted area, or administered systemically.

As utilized herein, the phrase “therapeutic agent(s)” refers to a numberof different drugs or agents available, as well as future agents thatmay be beneficial for use with the barrier layer of the presentinvention. Therapeutic agents can be added to the barrier layer 10,and/or the medical device in combination with the barrier layer 10 asdiscussed herein. The therapeutic agent component can take a number ofdifferent forms including anti-oxidants, anti-inflammatory agents,anti-coagulant agents, drugs to alter lipid metabolism,anti-proliferatives, anti-neoplastics, tissue growth stimulants,functional protein/factor delivery agents, anti-infective agents,anti-imaging agents, anesthetic agents, therapeutic agents, tissueabsorption enhancers, anti-adhesion agents, germicides, anti-septics,analgesics, prodrugs, and any additional desired therapeutic agents suchas those listed in Table 1 below.

TABLE #1 CLASS EXAMPLES Antioxidants Alpha-tocopherol, lazaroid,probucol, phenolic antioxidant, resveretrol, AGI-1067, vitamin EAntihyperten- Diltiazem, nifedipine, verapamil sive Agents Antiin-Glucocorticoids (e.g. dexamethazone, flammatory methylprednisolone),leflunomide, NSAIDS, ibuprofen, Agents acetaminophen, hydrocortizoneacetate, hydrocortizone sodium phosphate, macrophage-targetedbisphosphonates Growth Factor Angiopeptin, trapidil, suramin AntagonistsAntiplatelet Aspirin, dipyridamole, ticlopidine, clopidogrel, Agents GPIIb/IIIa inhibitors, abcximab Anticoagulant Bivalirudin, heparin (lowmolecular weight and Agents unfractionated), wafarin, hirudin,enoxaparin, citrate Thrombolytic Alteplase, reteplase, streptase,urokinase, TPA, citrate Agents Drugs to Alter Fluvastatin, colestipol,lovastatin, atorvastatin, Lipid amlopidine Metabolism (e.g. statins) ACEInhibitors Elanapril, fosinopril, cilazapril Antihyperten- Prazosin,doxazosin sive Agents Antiprolifera- Cyclosporine, cochicine, mitomycinC, sirolimus tives and micophenonolic acid, rapamycin, everolimus,tacrolimus, Antineoplastics paclitaxel, QP-2, actinomycin, estradiols,dexamethasone, methatrexate, cilostazol, prednisone, cyclosporine,doxorubicin, ranpirnas, troglitzon, valsarten, pemirolast, C- MYCantisense, angiopeptin, vincristine, PCNA ribozyme,2-chloro-deoxyadenosine Tissue growth Bone morphogeneic protein,fibroblast growth factor stimulants Promotion of Alcohol, surgicalsealant polymers, polyvinyl particles, 2- hollow organ octylcyanoacrylate, hydrogels, collagen, liposomes occlusion or thrombosisFunctional Insulin, human growth hormone, estradiols, nitric oxide,Protein/Factor endothelial progenitor cell antibodies delivery SecondProtein kinase inhibitors messenger targeting Angiogenic Angiopoetin,VEGF Anti-c Endostatin Angiogeni Inhibitation of Halofuginone, prolylhydroxylase inhibitors, C-proteinase Protein inhibitors Synthesis/ECMformation Antiinfective Penicillin, gentamycin, adriamycin, cefazolin,amikacin, Agents ceftazidime, tobramycin, levofloxacin, silver, copper,hydroxyapatite, vancomycin, ciprofloxacin, rifampin, mupirocin, RIP,kanamycin, brominated furonone, algae byproducts, bacitracin, oxacillin,nafcillin, floxacillin, clindamycin, cephradin, neomycin, methicillin,oxytetracycline hydrochloride, Selenium. Gene Delivery Genes for nitricoxide synthase, human growth hormone, antisense oligonucleotides LocalTissue Alcohol, H2O, saline, fish oils, vegetable oils, liposomesperfusion Nitric oxide NCX 4016 - nitric oxide donor derivative ofaspirin, Donor SNAP Derivatives Gases Nitric oxide, compound solutionsImaging Halogenated xanthenes, diatrizoate meglumine, diatrizoate Agentssodium Anesthetic Lidocaine, benzocaine Agents Descaling Nitric acid,acetic acid, hypochlorite Agents Anti-Fibrotic Interferon gamma-1b,Interluekin-10 Agents Immuno- Cyclosporine, rapamycin, mycophenolatemotefil, suppressive/ leflunomide, tacrolimus, tranilast, interferongamma-1b, Immuno- mizoribine modulatory Agents Chemothera- Doxorubicin,paclitaxel, tacrolimus, sirolimus, fludarabine, peutic Agents ranpirnaseTissue Fish oil, squid oil, omega 3 fatty acids, vegetable oils,Absorption lipophilic and hydrophilic solutions suitable for enhancingEnhancers medication tissue absorption, distribution and permeationAnti-Adhesion Hyaluronic acid, human plasma derived surgical Agentssealants, and agents comprised of hyaluronate and carboxymethylcellulosethat are combined with dimethylaminopropyl, ehtylcarbodimide,hydrochloride, PLA, PLGA Ribonucleases Ranpirnase Germicides Betadine,iodine, sliver nitrate, furan derivatives, nitrofurazone, benzalkoniumchloride, benzoic acid, salicylic acid, hypochlorites, peroxides,thiosulfates, salicylanilide Antiseptics Selenium AnalgesicsBupivicaine, naproxen, ibuprofen, acetylsalicylic acid

Some specific examples of therapeutic agents useful in theanti-restenosis realm include cerivastatin, cilostazol, fluvastatin,lovastatin, paclitaxel, pravastatin, rapamycin, a rapamycin carbohydratederivative (for example, as described in US Patent ApplicationPublication 2004/0235762), a rapamycin derivative (for example, asdescribed in U.S. Pat. No. 6,200,985), everolimus, seco-rapamycin,seco-everolimus, and simvastatin. With systemic administration, thetherapeutic agent is administered orally or intravenously to besystemically processed by the patient. However, there are drawbacks to asystemic delivery of a therapeutic agent, one of which is that thetherapeutic agent travels to all portions of the patient's body and canhave undesired effects at areas not targeted for treatment by thetherapeutic agent. Furthermore, large doses of the therapeutic agentonly amplify the undesired effects at non-target areas. As a result, theamount of therapeutic agent that results in application to a specifictargeted location in a patient may have to be reduced when administeredsystemically to reduce complications from toxicity resulting from ahigher dosage of the therapeutic agent.

Accordingly, an alternative to the systemic administration of atherapeutic agent is the use of a targeted local therapeutic agentdelivery approach. With local delivery of a therapeutic agent, thetherapeutic agent is administered using a medical device or apparatus,directly by hand, or sprayed on the tissue, at a selected targetedtissue location of the patient that requires treatment. The therapeuticagent emits, or is otherwise delivered, from the medical deviceapparatus, and/or carrier, and is applied to the targeted tissuelocation. The local delivery of a therapeutic agent enables a moreconcentrated and higher quantity of therapeutic agent to be delivereddirectly at the targeted tissue location, without having broadersystemic side effects. With local delivery, the therapeutic agent thatescapes the targeted tissue location dilutes as it travels to theremainder of the patient's body, substantially reducing or eliminatingsystemic side effects.

Targeted local therapeutic agent delivery using a medical device can befurther broken into two categories, namely, short term and long termranging generally within a matter of seconds or minutes to a few days orweeks to a number of months. Typically, to achieve the long termdelivery of a therapeutic agent, the therapeutic agent must be combinedwith a delivery agent, or otherwise formed with a physical impediment asa part of the medical device, to slow the release of the therapeuticagent.

Prior attempts to create films and drug delivery platforms, such as inthe field of stents, primarily make use of high molecular weightsynthetic polymer based materials to provide the ability to bettercontrol the release of the therapeutic agent. Essentially, the polymerin the platform releases the drug or agent at a predetermined rate onceimplanted at a location within the patient. Regardless of how much ofthe therapeutic agent would be most beneficial to the damaged tissue,the polymer releases the therapeutic agent based on properties of thepolymer. Accordingly, the effect of the therapeutic agent issubstantially local at the surface of the tissue making contact with themedical device having the coating. In some instances the effect of thetherapeutic agent is further localized to the specific locations of, forexample, stent struts or mesh pressed against the tissue location beingtreated. These prior approaches can create the potential for a localizedtoxic effect.

The barrier layer 10 of the present invention, however, makes use of thenatural oils to form a non-polymeric natural oil based therapeutic agentdelivery platform, if desired. Furthermore, the barrier layer 10 can beformed in a manner that creates the potential for controlled long termrelease of a therapeutic agent, while still maintaining the benefits ofthe natural oil component of the barrier layer 10.

More specifically, it is known that oil that is oxygenated becomes awaxy solid. Attempts have been made to convert the polyunsaturated oilsinto a wax or solid to allow the oil to adhere to a device for a longerperiod of time. One such approach applies the oil to the medical deviceand allows the oil to dry.

With the present invention, and in the field of soft tissueapplications, and in part because of the lipophilic mechanism enabled bythe bio-absorbable lipid based barrier layer 10 of the presentinvention, the uptake of the therapeutic agent is facilitated by thedelivery of the therapeutic agent to the cell membrane by thebio-absorbable barrier layer 10. Further, the therapeutic agent is notfreely released into the body fluids, but rather, is delivered directlyto the cells and tissue. In prior configurations using polymer basedcoatings, the drugs were released at a rate regardless of the reactionor need for the drug on the part of the cells receiving the drug.

In addition, when the oil provided to form the barrier layer 10 is anaturally occurring oil containing the omega-3 fatty acids (includingDHA and EPA), the process for forming the barrier layer 10 can betailored to avoid causing detrimental effects to the beneficialproperties of the omega-3 fatty acids, or at least effects toodetrimental to have any lasting effect. As described herein, certainproperties of the fatty acids may lose their effectiveness, howeverother desired properties are maintained. If there is no concern formaintaining the beneficial effects, the curing and other steps leadingto the formation of the barrier layer 10 can include steps that mayreduce some of the beneficial properties of the omega-3 fatty acids, asunderstood by one of ordinary skill in the art. Example embodimentsillustrating the formation and different configurations of the barrierlayer 10 are provided herein:

To summarize, the barrier layer 10 of the present invention serves as anon-polymeric biological oil barrier layer and can also serve as aphysical barrier layer if sufficiently cured. In accordance with theexample embodiments described herein, the barrier layer is formed of anon-polymeric cross-linked gel, which can be derived from fatty acidcompounds. The fatty acids include omega-3 fatty acids when the oilutilized to form the barrier layer is fish oil or an analog orderivative thereof. As liquid fish oil is heated, autoxidation occurswith the absorption of oxygen into the fish oil to create hydroperoxidesin an amount dependent upon the amount of unsaturated (C═C) sites in thefish oil. However, the (C═C) bonds are not consumed in the initialreaction. Concurrent with the formation of hydroperoxides is theisomerization of (C═C) double bonds from cis to trans in addition todouble bond conjugation. It has been demonstrated that hydroperoxideformation increases with temperature. Heating of the fish oil allows forcross-linking between the fish oil unsaturated chains using acombination of peroxide (C—O—O—C), ether (C—O—C), and hydrocarbon (C—C)bridges. The formation of the cross-links results in gelation of thebarrier layer after the (C═C) bonds have substantially isomerized intothe trans configuration. The (C═C) bonds can also form C—C cross-linkingbridges in the glyceride hydrocarbon chains using a Diels-AlderReaction. In addition to solidifying the barrier layer throughcross-linking, both the hydroperoxide and (C═C) bonds can undergosecondary reactions converting them into lower molecular weightsecondary oxidation byproducts including aldehydes, ketones, alcohols,fatty acids, esters, lactones, ethers, and hydrocarbons.

Accordingly, the barrier layer non-polymeric cross-linked gel derivedfrom fatty acid compounds, such as those of fish oil, includes across-linked structure of triglyceride and fatty acid molecules inaddition to free and bound glycerol, monoglyceride, diglyceride, andtriglyceride, fatty acid, anhydride, lactone, aliphatic peroxide,aldehyde, and ketone molecules. There are a substantial amount of esterbonds remaining after curing in addition to peroxide linkages formingthe majority of the cross-links in the gel. The barrier layer degradesinto fatty acid, short and long chain alcohol, and glyceride molecules,which are all non-inflammatory and likewise consumable by cells in thesoft tissue to which the barrier layer is applied. Thus, the barrierlayer is bio-absorbable.

FIGS. 2A, 2B, and 2C illustrate side views of multiple differentembodiments of the barrier layer 10 when cured into a flexiblecross-linked gel. In FIG. 2A, a barrier layer 10A is shown having twotiers, a first tier 20 and a second tier 22. The first tier 20 and thesecond tier 22 as shown are formed of different materials. The differentmaterials can be different forms of fish oil, different naturallyoccurring oils other than fish oil, or therapeutic components as will bediscussed later herein. The different materials bind together to formthe barrier layer 10A.

FIG. 2B shows a barrier layer 10B having a first tier 24, a second tier26, and a third tier 28. In the embodiment shown, each of the tiers 24,26, and 28 is formed of the same material. The plurality of tiersindicates the ability to create a thicker barrier layer 10 if desired.The greater the number of tiers, the thicker the resulting film. Thethickness of the barrier layer 10 can have an effect on the overallstrength and durability of the barrier layer 10. A thicker film isgenerally stronger and more durable. In addition, the thickness of thebarrier layer 10 can also affect the duration of time that the barrierlayer 10 lasts after implantation. A thicker barrier layer 10 providesmore material to be absorbed by the body, and thus will last longer thana thinner barrier layer 10. One of ordinary skill in the art willappreciate that the thickness of the barrier layer 10 can vary both byvarying the thickness of each tier 24, 26, and 28, and by varying thenumber of tiers 24, 26, and 28. Accordingly, the present invention isnot limited to the particular layer combinations illustrated.

FIG. 2C shows another barrier layer 10C, having four tiers, a first tier30, a second tier 32, a third tier 34, and a fourth tier 36. In thisexample embodiment, the first tier 30 and the third tier 34 are formedof the same material, while the second tier 32 and the fourth tier 36are formed of a material different from each other and different fromthat of the first tier 30 and the third tier 34. Accordingly, thisembodiment illustrates the ability to change the number of tiers, aswell as the material used to form each of the tiers 30, 32, 34, and 36.Again, the different materials can be derived from different forms offish oil, different naturally occurring oils other than fish oil, ortherapeutic components as will be discussed later herein.

FIGS. 3A through 3F show additional embodiments or configurations of thebarrier layer 10. The embodiments include barrier layer 10D in acircular configuration, barrier layer 10E in an oval configuration,barrier layer 10F in a U-bend configuration, barrier layer 10G in asquare configuration having a circular aperture, barrier layer 10H in awave configuration, and barrier layer 10I in an irregular shapeconfiguration. Each of the configurations of the barrier layer 10Dthrough 10I represent different types of configurations. Theconfigurations illustrated are by no means the only possibleconfigurations for the barrier layer 10. One of ordinary skill in theart will appreciate that the specific shape or configuration of thebarrier layer 10 can vary as desired. A more prevalent configuration isthe rectangular or oblong configuration of FIG. 1. However, FIGS. 3Athrough 3F illustrate a number of different alternative embodiments, andindicate some of the many possible configurations.

FIG. 4 is a flowchart illustrating one example method for the formationof the barrier layer 10. A surface is provided having a release agent(step 100). The surface can be prepared by the application of therelease agent, or the release agent can be pre-existing. The releaseagent can be a number of different solutions, including for example,polyvinyl alcohol (PVA). The release agent can be applied in a number ofdifferent ways as well, including but not limited to spraying, dipping,coating, painting, and the like. It should be noted that the releaseagent can be applied to the surface immediately prior to the remainingsteps or well in advance of the remaining steps, so long as when theremaining steps are executed there is a release agent on the surface. Itshould further be noted that the need of a release agent can beeliminated if the surface itself has inherent characteristics similar toone having a release agent. Specifically, the surface can instead have aTeflon® coating, or other similar more permanent release surface. Insuch an instance, there is no need for a release agent, or subsequentremoval of the release agent from the barrier layer formed.

An oil component is applied to the surface on top of the release agent(step 102). As noted previously, the oil component can be a naturallyoccurring oil, such as fish oil, cod liver oil, cranberry oil, or otheroils having desired characteristics. In addition, the oil component canbe an oil composition, meaning a composition containing oil in additionto other substances. For example, the oil composition can be formed ofthe oil component in addition to a solvent and/or a preservative.Solvents can include a number of different alternatives, includingethanol or N-Methyl-2-Pyrrolidone (NMP). The preservative can alsoinclude a number of different alternatives, including vitamin E. One ofordinary skill in the art will appreciate that there are a number ofdifferent solvents and preservatives available for use with the oilcomponent to form the oil composition, and as such the present inventionis not limited to only those listed in the examples herein. The solventcan be useful to alter the physical properties of the oil, as well asprepare the oil for combination with a therapeutic agent as describedbelow. The preservative can also be useful in altering the physicalproperties of the oil component, as well as protecting some of thebeneficial properties of the oil component during certain curingprocesses. Such beneficial properties include the healing andanti-inflammatory characteristics previously mentioned.

The oil component can be combined with one or more therapeutic agents toform an oil composition. Thus, if the added therapeutic benefit of aparticular therapeutic agent or agents is desired, the therapeuticagent(s) can be added to the oil component prior to application to thesurface, along with the oil component during application to the surface(including mixing with the oil component prior to application), or afterthe oil component has been applied (step 104). The differentalternatives for adding the therapeutic agent(s) are determined in partbased on the desired effect and in part on the particular therapeuticagent(s) being added. Some therapeutic agents may have reduced effect ifpresent during a subsequent curing step. Some therapeutic agents may bemore useful intermixed with the oil component to extend the releaseperiod, or applied to the surface of the oil component, resulting in afaster release because of increased exposure. One of ordinary skill inthe art will appreciate that a number of different factors, such asthose listed above in addition to others, can influence when in theprocess the therapeutic agent is added to the oil component, or thebarrier layer 10. Accordingly, the present invention is not limited tothe specific combinations described, but is intended to anticipate allsuch possible variations for adding the therapeutic agent(s).

For example, if 80% of a therapeutic agent is rendered ineffectiveduring curing, the remaining 20% of therapeutic agent, combined with anddelivered by the barrier can be efficacious in treating a medicaldisorder, and in some cases have a relatively greater therapeutic effectthan the same quantity of agent delivered with a polymeric or other typeof coating or barrier. This result can be modified with the variance ofalpha-tocopherol to protect the therapeutic agent during the curingprocess, and then slow and extend the delivery of the therapeutic agentduring absorption of the barrier layer into the tissue.

The oil component (or composition if mixed with other substances) isthen hardened into the barrier layer 10 (step 106). The step ofhardening can include hardening, or curing, such as by introduction ofUV light, heat, oxygen or other reactive gases, chemical curing, orother curing or hardening method. The purpose of the hardening or curingis to transform the more liquid consistency of the oil component or oilcomposition into a more solid film, while still maintaining sufficientflexibility to allow bending and wrapping of the film as desired.However, the hardening process as described herein does not refer to orinclude the process of hydrogenation.

After the barrier layer 10 has formed, another determination is made asto whether therapeutic agents should be applied to the film. If desired,the therapeutic agent(s) is added to the barrier layer 10 (step 108).Subsequently, the barrier layer 10 is removed from the surface (step110). Once again, there is opportunity to apply a therapeutic agent(s)to the barrier layer 10 on one or both sides of the barrier layer 10. Ifsuch therapeutic agent(s) is desired, the therapeutic agent(s) isapplied (step 112). The additional therapeutic agent can also be appliedin the form of a non-cured or minimally cured oil, such as fish oil. Theoil can likewise include other therapeutic agents mixed therewith. Theresulting structure of such an application forms the underlying barrierlayer 10 that is cured to form the film, with a top coating of oil andpotentially additional therapeutic agent layered on top. This structureenables the provision of a short term release of therapeutic from theoil top layer combined with a longer term release from the cured film,which takes more time to degrade.

After application of the therapeutic agent(s), or after the barrierlayer 10 is removed from the surface, the barrier layer 10 issterilized. The sterilization process can be implemented in a number ofdifferent ways. For example, sterilization can be implemented utilizingethylene oxide, gamma radiation, E beam, steam, gas plasma, or vaporizedhydrogen peroxide (VHP). One of ordinary skill in the art willappreciate that other sterilization processes can also be applied, andthat those listed herein are merely examples of sterilization processesthat result in a sterilization of the barrier layer 10, preferablywithout having a detrimental effect on the barrier layer.

It should be noted that the oil component or oil composition can beadded multiple times to create multiple tiers in forming the barrierlayer 10. For example, if a thicker barrier layer 10 is desired,additional tiers of the oil component or oil composition can be addedafter steps 100, 104, 106, 108, 110, or 112. Different variationsrelating to when the oil is hardened and when other substances are addedto the oil are possible in a number of different process configurations.Accordingly, the present invention is not limited to the specificsequence illustrated. Rather, different combinations of the basic stepsillustrated are anticipated by the present invention.

FIGS. 5A and 5B illustrate the barrier layer 10 and a medical device inthe form of a mesh 40. In FIG. 5A, the barrier layer 10 and mesh 40 areshown in exploded view, while FIG. 5B shows the barrier layer 10 coupledwith the mesh 40. The mesh 40 is merely one example medical device thatcan be coupled with the barrier layer 10. In the instance of the mesh40, it can be useful to have one side of the mesh support a roughersurface to encourage tissue in-growth, and the other side of the meshwith an anti-adhesion, anti-inflammatory, and/or non-inflammatorysurface to prevent the mesh from injuring surrounding tissue or causinginflammation. The coupling of the barrier layer 10 with the mesh 40achieves such a device.

As understood by one of ordinary skill in the art, the properties of themesh 40 and the barrier layer 10 can vary. There may be a requirementfor the mesh 40 to have one side, or a portion of a side, that hasanti-adhesion properties for a period of several days. Alternatively,multiple sides of the mesh 40 may be required to have anti-adhesionproperties. As such, the barrier layer 10 can be applied to all sides,or portions of sides, or portions of one side of the mesh 40.

In addition, the requirement may be for the anti-adhesion properties tolast several weeks, or even longer. Accordingly, the rate of degradationcan also be varied by changing such properties as amount ofcross-linking, thickness, and existence of additives, such as vitamin Ecompounds to achieve longer or shorter term anti-adhesion properties. Inaddition, there may be a desire to include a therapeutic agent to reduceinflammation, provide antibiotic therapy, or other therapeutic measures,in combination with the use of the mesh 40. Accordingly, the therapeuticagent(s) can be added to the barrier layer 10 to achieve the desiredcontrolled release of the therapeutic agent after implantation. Aspreviously described, combinations of cured oils top coated with lessercured or non-cured oils and therapeutic agents can form the barrierlayer 10.

The particular properties or characteristics of the mesh 40 aredetermined based on the desired use of the mesh 40. A commonimplementation is for the mesh 40 to be formed of a bio-compatiblematerial, such as polypropylene, however other bio-compatible materialscan be utilized, such as a mesh formed of the same or similar substanceas the barrier layer 10 (i.e., oil based).

FIG. 6 is a flowchart illustrating one example method for forming themesh 40 and barrier layer 10 combination. The medical device is provided(step 150). The medical device can be, for example, the mesh 40.

A determination is made as to whether a release agent should be added tothe medical device to aid in removing the device from its location(e.g., on a surface) after combination with the barrier layer 10. If arelease agent is required, the release agent is applied to the medicaldevice (step 152). An example release agent for such an application ispolyvinyl alcohol.

The medical device is then combined with the barrier layer 10 (step154). Depending on the particular medical device, the combination withthe barrier layer 10 can be implemented more efficiently by eitherapplying the barrier layer 10 to the medical device, or placing themedical device on the barrier layer 10. For example, in the case of themesh 40, the mesh 40 can be placed on top of the barrier layer 10, orthe barrier layer 10 can be placed on top of the mesh 40.

The medical device and the barrier layer are then cured to create a bond(step 156). The curing process can be one of several known processes,including but not limited to applying heat, or UV light, or chemicalcuring, to cure the barrier layer. After curing, if there is any releaseagent present, the release agent is washed away using water, or someother washing agent (step 158).

FIG. 7 is a flowchart illustrating another example method of forming amedical device with a barrier layer. A surface is prepared with arelease agent, such as PVA (step 170). The medical device is placed onthe surface (step 172). In the example embodiment, the medical device isthe mesh 40. The oil component or oil composition is applied to themedical device (step 174). In the instance of the mesh 40, the oilcomponent or oil composition is poured or sprayed onto the mesh 40. Thecombined oil component/composition and mesh 40 are then cured (step 176)using methods such as application of heat, UV light, oxygen and otherreactive gases, chemical cross-linker, or hardening processes, to formthe barrier layer in combination with the mesh 40. The combined barrierlayer and mesh are then removed from the surface (step 178) and therelease agent is washed away (step 180).

As with the method of FIG. 6, if desired, a therapeutic agent can beadded to the oil component or oil composition at any point along theprocess forming the combined barrier layer 10 and mesh 40, includingbeing a component of the oil composition. As discussed previously,consideration must be given as to whether the therapeutic agent may beaffected by the curing process, or other aspects of the process.

Furthermore, the formation of the oil composition can be done inaccordance with different alternatives to the methods described. Forexample, prior to forming the barrier layer 10, a preservative and/orcompatibilizer, such as Vitamin E can be mixed with the naturallyoccurring oil component to form the oil composition. A solvent can bemixed with a therapeutic agent, and then added to the naturallyoccurring oil to form the oil composition. The solvent can be chosenfrom a number of different alternatives, including ethanol orN-Methyl-2-Pyrrolidone (NMP). The solvent can later be removed withvacuum or heat.

In addition, it should again be noted that the oil component or oilcomposition can be added multiple times to create multiple tiers informing the barrier layer 10. If a thicker barrier layer 10 is desired,additional tiers of the oil component or oil composition can be addedafter steps 174 and 176. Different variations relating to when the oilis hardened and when other substances are added to the oil are possiblein a number of different process configurations. Accordingly, thepresent invention is not limited to the specific sequence illustrated.Rather, different combinations of the basic steps illustrated areanticipated by the present invention.

Depending on the type of therapeutic agent component added to thebarrier layer 10, the resulting barrier layer 10 can maintain itsbio-absorbable characteristics if the therapeutic agent component isalso bio-absorbable.

The therapeutic agent component, as described herein, has some form oftherapeutic or biological effect. The oil component or oil compositioncomponent can also have a therapeutic or biological effect.Specifically, the barrier layer 10 (and its oil constituents) enable thecells of body tissue of a patient to absorb the barrier layer 10 itself,rather than breaking down the film and disbursing by-products of thefilm for ultimate elimination by the patient's body.

As previously stated, and in accordance with embodiments of the presentinvention, the barrier layer 10 is formed of a naturally occurring oil,or composition including a naturally occurring oil, such as fish oil,cod liver oil, cranberry oil, and the like. A characteristic of thenaturally occurring oil is that the oil includes lipids, whichcontributes to the lipophilic action described later herein, that ishelpful in the delivery of therapeutic agents to the cells of the bodytissue. In addition, the naturally occurring oil can include theessential omega-3 fatty acids in accordance with several embodiments ofthe present invention.

It should also be noted that the present description makes use of themesh 40 as an example of a medical device that can be combined with thebarrier layer 10 of the present invention. However, the presentinvention is not limited to use with the mesh 40. Instead, any number ofother implantable medical devices can be combined with the barrier layer10 in accordance with the teachings of the present invention. Suchmedical devices include catheters, grafts, balloons, prostheses, stents,other medical device implants, and the like. Furthermore, implantationrefers to both temporarily implantable medical devices, as well aspermanently implantable medical devices.

FIGS. 8A, 8B, and 8C illustrate some of the other forms of medicaldevices mentioned above in combination with the barrier layer 10 of thepresent invention. FIG. 8A shows a graft 50 with the barrier layer 10coupled or adhered thereto. FIG. 8B shows a catheter balloon 52 with thebarrier layer 10 coupled or adhered thereto. FIG. 8C shows a stent 54with the barrier layer 10 coupled or adhered thereto. Each of themedical devices illustrated, in addition to others not specificallyillustrated or discussed, can be combined with the barrier layer 10using the methods described herein, or variations thereof. Accordingly,the present invention is not limited to the example embodimentsillustrated. Rather the embodiments illustrated are merely exampleimplementations of the present invention.

Example #1

An embodiment of the present invention was implemented in a rat model todemonstrate the performance of the barrier layer of the presentinvention relative to other known surgical mesh devices. The deviceswere implanted in a rat to repair abdominal wall defects. Healingcharacteristics, adhesion formation and tenacity, and inflammatoryresponse associated with these materials were compared.

A polypropylene mesh material (ProLite™) provided by Atrium MedicalCorporation of Hudson, N.H., coated with one embodiment of the barrierlayer described herein. The polypropylene mesh with barrier layer wascompared with a bare polypropylene control mesh, and DualMesh®biomaterial provided by W. L. Gore & Associates, Inc.

Five samples of each mesh type were implanted according to a randomschedule. On the day of surgery, the animals were anesthetized with aninjection of 50 mg/kg Nembutal IP. The animal was prepped for surgery,and a midline abdominal incision was made. A portion of rectus muscleand fascia was removed leaving an approximately 20 mm×30 mm fullthickness defect in the abdominal wall. Using 4-0 Prolene, theappropriate patch was sutured into place repairing the existing defect.An overlap of mesh was placed over the defect to ensure proper repair,with the mesh samples being 2.5 cm×3.5 cm in size. The mesh was placedsuch that the smoother side was toward the viscera in the case of thepolypropylene mesh with barrier layer, and the appropriate side of theGore DualMesh was also placed towards the viscera. Suture knots weremade on the abdominal wall side of the implant rather than the visceralside as to not interfere with tissue attachment. The mesh was suturedaround the entire perimeter to ensure adequate placement. The subdermaland subcutical layers were closed with Vicryl. The skin was closed usingsurgical staples. The animals received Buprenorphine for pain. The meshwas explanted at approximately 30 days.

Sample Explanation:

Approximately 30 days after implantation, the animals were againanesthetized for explant of the mesh samples. The skin staples wereremoved, and a vertical incision through the skin and subcutaneoustissue was made lateral to both the implantation site and patch. Throughthis incision, the implant was inspected and photos were taken todocument adhesion formation. Upon gross examination, the sameinvestigator evaluated each sample for adherent intraperitoneal tissuesand assigned an adhesion grade to each sample (Jenkins S D, Klamer T W,Parteka J J, and Condon R E. A comparison of prosthetic materials usedto repair abdominal wall defects. Surgery 1983; 94:392-8). In general,the adhesions were scored as: 0—no adhesions; 1—minimal adhesions thatcould be freed by gentle blunt dissection; 2—moderate adhesions thatcould be freed by aggressive blunt dissection; 3—dense adhesion thatrequire sharp dissection.

Once the gross evaluation was complete, the mid-portion of the abdominalcavity was excised including the implant, and adhesive tissue notcompletely separated from the implant, and the overlying subcutaneousand skin. Sections were then fixed and processed for histologicalevaluation. The histology samples were stained with Hematoxylin andEosin, Trichrome, GS1, and Vimentin.

Polypropylene Mesh Control:

These patches had a mean adhesion score of 2.1. Adhesions consisted ofomentum, epididymal fat, and one had intestinal adhesions. Many of theadhesions were at the edges of the patch/tissue interface. The adhesionsrequired aggressive blunt dissection to remove them. There was amoderate inflammatory response associated around the fibers of the mesh.There was a tight association of fat to the implant surface on theperitoneal cavity side, meaning the adhesions were not fully removed.

Gore DualMesh® Control:

Patches were entirely covered with adhesions. The adhesions consisted ofepidiymal fat, omentum and bowel. The mean adhesion score was 2.9. Therewas a capsule covering the entire patch that needed sharp dissection tofree from material. Adhesions pulled free from capsule with bluntdissection. A moderate to severe inflammatory response was observed inassociation with the skin side of the implant. The thin fibrous capsuleon the peritoneal side of the implant was avascular and in some implantswas loosely adherent to associated tissue.

Polypropylene Mesh with Barrier Layer (Embodiment of Present Invention):

These patches had a mean adhesion score of 1.6. Adhesions includedepididymal fat and some omentum. The adhesions dissociated from thepatches relatively easily. There was a mild to minimal inflammatoryresponse associated with the exposed polypropylene fibers of thismaterial. Vimentin staining showed a layer of mesothelial cells formedon the tissue on the peritoneal cavity side of the implant.

The polypropylene mesh with barrier layer in accordance with oneembodiment of the present invention showed good results in terms ofadhesion minimization, tenacity of adhesions formed, and a lowinflammatory response. The coated mesh product was also easy to handle,place, and suture for repair of an abdominal wall defect in this model.

The oil component itself, in the form of fish oil for example, canprovide therapeutic benefits in the form of reduced inflammation, andimproved healing, if the fish oil composition is not substantiallymodified during the process that takes the naturally occurring fish oiland forms it into the barrier layer 10. Some prior attempts to usenatural oils as coatings have involved mixing the oil with a solvent, orcuring the oil in a manner that destroys the beneficial aspects of theoil. The solvent utilized in the example bather layer 10 embodiment ofthe present invention (NMP) does not have such detrimental effects onthe therapeutic properties of the fish oil. Thus the benefits of theomega-3 fatty acids, and the EPA and DHA substances are substantiallypreserved in the barrier layer of the present invention.

Therefore, the barrier layer 10 of the present invention includes thebio-absorbable naturally occurring oil (i.e., fish oil). The barrierlayer 10 is thus able to be absorbed by the cells of the body tissue.With the present invention, because of the lipophilic action enabled bythe bio-absorbable lipid based barrier layer 10 of the presentinvention, the intake by the tissue cells of the barrier layer 10, andany therapeutic agent component, is substantially controlled by thecells themselves. In configurations using polymer based materials, thedrugs were released at a rate regardless of the reaction or need for thedrug on the part of the cells receiving the drug. With the barrier layer10 of the present invention, the cells can intake as much of the barrierlayer 10, and correspondingly the therapeutic agent, as is needed by thedamaged cell requiring treatment.

In addition, the bio-absorbable nature of the barrier layer 10 resultsin the barrier layer 10 being completely absorbed over time by the cellsof the body tissue. There is no break down of the barrier layer 10 intosub parts and substances that are inflammatory and are eventuallydistributed throughout the body and in some instances disposed of by thebody, as is the case with biodegradable synthetic polymer coatings. Thebio-absorbable nature of the barrier layer 10 of the present inventionresults in the barrier layer 10 being absorbed, leaving only the medicaldevice structure, if the barrier layer 10 is not implanted alone. Thereis no inflammatory foreign body response to the barrier layer 10.

In addition, the barrier layer 10 provides a lubricious and/oranti-adhesive surface against tissue. The barrier layer 10 itself canprovide an anti-adhesion barrier between two sections of tissue, or thebarrier layer 10 can form an anti-adhesion surface on a medical device,such as the mesh 40. The use of the naturally occurring oil, such asfish oil, provides extra lubrication to the surface of the medicaldevice, which helps to reduces injury. With less injury, there is lessof an inflammatory response, and less healing required. Likewise thefatty acid derived cross-linked gel that makes up the barrier layermaintains anti-inflammatory properties which also substantially lowersthe inflammatory response of the tissue. The reduced inflammation alsoreduces adhesions.

Numerous modifications and alternative embodiments of the presentinvention will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present invention. Details ofthe structure may vary substantially without departing from the spiritof the invention, and exclusive use of all modifications that comewithin the scope of the appended claims is reserved. It is intended thatthe present invention be limited only to the extent required by theappended claims and the applicable rules of law.

What is claimed is:
 1. A method of making a barrier layer on at least aportion of a medical device structure, the method comprising the stepsof: providing a medical device structure; and creating a barrier layerformed on at least a portion of the medical device structure; whereinthe barrier layer is formed of a biological oil or oil compositioncomprising a cured fish oil, wherein the cured fish oil is hydrolysableby lipase and comprises fatty acids and glycerides, wherein two or moreof the fatty acids are cross-linked to each other by ester bonds in asubstantially random configuration so that the barrier layer provides abiological oil barrier and a physical anti-adhesion barrier, wherein thebarrier layer is solid but flexible, and wherein the barrier layerdegrades into non-inflammatory substances.
 2. The method of claim 1,wherein creating the barrier layer comprises: applying the oil or oilcomposition to the medical device structure; and curing the oil or oilcomposition on the medical device structure to form the barrier layer.3. The method of claim 2, further comprising partially curing thebiological oil or oil composition prior to applying the oil or oilcomposition to the medical device structure to thicken the oil or oilcomposition.
 4. The method of claim 1, further comprising applying theoil or oil composition using multiple tiers.
 5. The method of claim 1,further comprising applying an additional tier of oil or oil compositionafter curing the oil or oil composition on the medical device.
 6. Themethod of claim 1, wherein the cross-linked gel is hydrophobic and isformed on a surface of the medical device structure that is providedwith a release agent.
 7. The method of claim 1, wherein the barrierlayer further comprises alpha-tocopherol.
 8. The method of claim 1,further comprising adding at least one therapeutic agent to the barrierlayer.
 9. The method of claim 1, wherein the barrier layer comprises afirst tier configured on the medical device structure and a second tierconfigured on the first tier, wherein the first tier is cured to agreater extent than the second tier.
 10. The method of claim 1, whereinthe barrier layer comprises a first tier configured on the medicaldevice structure and a second tier configured on the first tier, whereinthe second tier is cured to a greater extent than the first tier. 11.The method of claim 1, wherein the barrier layer is configured toprovide controlled release of a therapeutic agent component.
 12. Themethod of claim 1, wherein the barrier layer is bio-absorbable.
 13. Themethod of claim 1, wherein the biological oil barrier layer maintainsanti-inflammatory properties.
 14. The method of claim 1, wherein thebarrier layer further comprises alpha tocopherol or a derivative oranalog thereof.
 15. The method of claim 1, wherein the medical devicecomprises a biocompatible mesh.
 16. The method of claim 1, whereincuring comprises applying a curing mechanism selected from a group ofcuring mechanisms consisting of heat and UV light.
 17. The method ofclaim 1, further comprising sterilizing the barrier layer and medicaldevice with a method of sterilization selected from a group of methodsof sterilization consisting of ethylene oxide, gamma radiation, e-beam,steam, gas plasma, and vaporized hydrogen peroxide (VHP).
 18. The methodof claim 1, wherein the barrier layer created comprises the cured fishoil and uncured fish oil.